This invention relates to lung surfactants, stable surfactant protein compositions and formulations, and methods for the preparation and assay thereof.
Respiratory distress syndrome (RDS), also known as hyaline membrane disease, is a major cause of morbidity and mortality of the prematurely born infant. RDS is believed to be caused primarily by a deficiency of lung surfactant--a lipid-protein mixture which coats the airspaces of the lung--thereby reducing the surface tension and preventing airspace collapse. The principal component of lung surfactant--dipalmitoylphosphatidylcholine (DPPC)--was identified several years ago (Klaus, et al ., Proc. Natl. Acad. Sci. USA 47:1858, 1961; Avery, et al., Am. J. Dis. Child. 97:517, 1959). It is believed that administration of lung surfactant to an individual having or at risk of developing RDS is a desirable therapy, and the literature discloses various clinical studies of therapeutic administration of different lung surfactant preparations.
The literature contains various lung surfactant protein preparations, including those with DPPC. Generally, preparations can be classified into five types. These include 1) natural human surfactant (purified from human amniotic fluid), (Merritt, et al., N. Engl. J. Med. 315:787, 1986,), 2) semisynthetic surfactant (prepared by combining DPPC and high density lipoprotein), (Halliday, et al., Lancet 1:476, 1984), 3) animal lung surfactant (isolated by organic extraction of the whole lung or lavage fluid), (Fujiwara, supra; Enhorning, et al., Pediatrics 76:145, 1985; Kwong, et al., Pediatrics 76:585, 1985), and 4) purified human surfactant apoproteins (SP-A, SP-B, and/or SP-C purified from natural sources or derived by recombinant DNA technology; see Jobe et al., Am. Rev. Resp. Dis. 136:1032, 1987, and Glasser et al., J. Biol. Chem. 263:10326, 1988) which are reconstituted with surfactant lipids (Revak, et al., J. Clin. Invest. 81:826, 1987).
It has been observed that lung surfactant protein tends to aggregate over time. It is therefore an object of this invention to provide more stable lung surfactant protein compositions and formulations, and methods for making same. It is a further object of this invention to provide lung surfactant protein compositions and formulations with improved biological properties and therapeutic efficacy.
It is also believed desirable for certain therapeutic uses that the surfactant administered have substantially the same structure as natural mammalian surfactant. It is therefore an additional object of this invention to provide lung surfactant protein similar in structure to naturally occurring surfactants.